Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factors and prostaglandins protect the gastric mucosa against stress-induced lesions but their role in the recovery of the mucosa from these lesions has been little studied. We evaluated gastric mucosa lesions, gastric blood flow, mucosal generation of prostaglandin E2 and mucosal gene expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) as well as constitutive prostaglandin cyclooxygenase-1 and inducible cyclooxygenase-2 and the effect of the inhibition of these enzymes on the recovery of mucosa from the stress-induced lesions. Rats were exposed to 3.5 h of water immersion and restraint stress and killed at 0, 2, 4, 6, 8, 12 and 24 h after stress. The number of gastric lesions was determined and gastric blood flow was measured by H2-gas clearance. Gastric acid secretion was tested in separate gastric fistula rats. Gastric mucosa biopsies were taken for determination of immunoreactive EGF and TGF alpha. Expression of EGF and TGF alpha mRNA and cyclooxygenase-1 and cyclooxygenase-2 mRNA was also determined by reverse-transcriptase polymerase chain reaction. The number of gastric lesions induced by 3.5 h stress averaged approximately 20 per rat and declined significantly at 2, 4, 6, 8 and 12 h, to disappear almost completely after 24 h. This was accompanied by a gradual rise in gastric blood flow, mucosal generation of prostaglandin E2 and mucosal EGF and TGF alpha contents, while the increased gastric acid secretion returned to normal. In the intact mucosa, EGF mRNA was not detected but TGF alpha mRNA was found in measurable amounts. Following exposure to stress, the expression of both these factors was significantly increased. Similarly, the expression of cyclo-oxygenase-1 and cyclooxygenase-2 mRNA was detected in the oxyntic mucosa at all time intervals after exposure to stress. Indomethacin (5 mg/kg i.p.), an inhibitor of cyclooxygenase-1 and cyclooxygenase-2, and meloxicam (1 mg/kg i.p.), an inhibitor of cyclooxygenase-2, both prolonged the healing of stress lesions and reduced the gastric blood flow, while enhancing gastric acid secretion at all times tested. We conclude that healing of stress lesions results in the restoration gastric blood flow and mucosal prostaglandin generation and that these effects are accompanied by overexpression of EGF and TGF alpha as well as cyclooxygenase-1 and cyclooxygenase-2 mRNA and by increased biosynthesis of gastroprotective prostaglandin.
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PMID:Activation of genes for growth factors and cyclooxygenases in rat gastric mucosa during recovery from stress damage. 954 93

Cyclooxygenase-2 (Cox-2), an inducible form of the enzyme that catalyzes the first step in the synthesis of prostanoids, has been shown to be overexpressed in a wide range of tumors and possesses proangiogenic and antiapoptotic properties. To understand the molecular mechanism of Cox-2 action we used adenovirus-mediated transfer of rat Cox-2 cDNA into renal rat mesangial cells and determined the differential gene expression using cDNA microarrays. One of the several genes that were highly up-regulated by over expressed Cox-2 was MDR1. MDR1 or P-glycoprotein (P-gp), the product of the MDR1 gene, is implicated as the primary cause of multidrug resistance (MDR) in tumors where it acts as an efflux pump for chemotherapeutic agents. It is also expressed in normal tissues of the liver and kidney where it functions to actively transport lipophilic xenobiotics. Reverse transcriptase-PCR analysis confirmed the results of the microarray, showing increased mRNA levels for MDR1 in Cox-2 overexpressing cells. This increase in mRNA translated to an increase in MDR1 protein expression, which was dose-dependent on Cox-2 expression. Furthermore, using rhodamine 123 efflux assay we observed a significant increase in P-gp activity in Cox-2 overexpressing renal mesangial cells. The specific Cox-2 inhibitor NS398 was able to block the Cox-2-mediated increase in MDR1 expression and activity, suggesting that Cox-2 products may be implicated in this response. These results prove the existence of a causal link between Cox-2 and P-gp activity, which would have implications for kidney function and multidrug resistance in tumors where Cox-2 is overexpressed.
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PMID:Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. 1213 26

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38alpha and p38beta2 MAPK mRNA in rat cardiac myocytes. Interleukin-1beta induced the phosphorylation of p38alpha and p38beta2 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38beta2 MAPK inhibited interleukin-1beta-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38alpha and p38beta2 MAPK inhibitor, SB202190, attenuated interleukin-1beta-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38beta2 MAPK, in the absence of interleukin-1beta, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1beta-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.
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PMID:MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. 1264 65

Previously we have shown that dietary conjugated linoleic acid (CLA) significantly decreased colon tumor incidence in rats injected with 1,2-dimenthylhydrazine (DMH). The present study was performed to explore the mechanisms responsible for the anticarcinogenic effect of CLA. Four groups of rats received either vehicle or intramuscular injections of DMH at the dose of 15 mg/kg body weight twice per week for 6 weeks and were fed a diet containing either 0% or 1.0% CLA ad libitum for 14 weeks. Dietary CLA decreased cellular proliferation and induced apoptosis in the colonic mucosa of both vehicle and DMH-treated rats. Mucosal levels of prostaglandin (PG) E(2), thromboxane B(2), and 1,2-diacylglycerol decreased in rats fed the 1% CLA diet, whereas cyclooxygenase-2 levels were not affected. Arachidonate content of mucosal phospholipids decreased significantly in rats fed the 1% CLA diet. Reverse transcriptase-polymer chain reaction analysis revealed that the Bax/Bcl-2 transcript ratio was significantly increased in rats fed 1% CLA. To examine whether the 1% CLA diet reduces tumor incidence, the DMH-treated rats were continuously fed the assigned diets for 30 weeks. Tumor incidence was significantly decreased in the CLA-fed group. In conclusion, our findings are consistent with the hypothesis that CLA decreases the incidence of colon cancer by decreasing cellular proliferation and inducing apoptosis of the colonic mucosa. These effects may be due in part to decreased PGE(2) levels and increased Bax/Bcl-2 ratios.
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PMID:Dietary conjugated linoleic acid increases the mRNA ratio of Bax/Bcl-2 in the colonic mucosa of rats. 1506 16

Cyclooxygenase-2 (COX-2) is considered to be a target for anticancer therapy. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP-1-mediated activation of COX-2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP-1-mediated induction of COX-2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c-Jun binding to the COX-2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c-Jun. HDAC inhibitors suppressed the induction of c-jun transcription by blocking the recruitment of the preinitiation complex (RNA polymerase II and TFIIB) to the c-jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP-1-mediated stimulation of c-jun expression. Because HDAC inhibitors suppressed the induction of c-jun gene expression, resulting in reduced COX-2 transcription, it was important to determine whether other known AP-1 target genes were also modulated. Cyclin D1 and collagenase-1 are AP-1-dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase-1 transcription by inhibiting the binding of c-Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c-jun transcription by inhibiting the recruitment of the preinitiation complex to the c-jun promoter. This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.
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PMID:Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2. 3190 Mar 76

The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 micromol/L), celecoxib (1 and 10 micromol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-kappaB activation. Growth inhibition and apoptosis were significantly (P < 0.05) higher in BxPC-3, HPAC, and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib. However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 micromol/L) and celecoxib (10 micromol/L) compared with celecoxib- or erlotinib-treated cells. Celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-kappaB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) Celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-kappaB inactivation contributes to the potentiation of erlotinib by celecoxib.
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PMID:Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy. 1637 9

Helicobacter pylori is an important risk factor of gastric cancer (GC). Although many H. pylori virulence factors have been reported, the pathogenic mechanism by which H. pylori infection causes GC remains unclear. The aims of this study were to identify GC-related antigens from H. pylori and characterize their roles in the development of GC. As GC and duodenal ulcer (DU) are considered clinically divergent, we compared two-dimensional immunoblots of an acid-glycine extract of H. pylori probed with serum samples from 15 patients with GC and 15 with DU to find GC-related antigens, which were subsequently identified by mass spectrometry. Many protein spots were recognized by more than one serum, and 24 of these were better recognized by GC sera. The proteins showing higher frequency of recognition in GC group are threonine synthase, rod shape-determining protein, S-adenosylmethionine synthetase, peptide chain release factor 1, DNA-directed RNA polymerase alpha subunit, co-chaperonin GroES (monomeric and dimeric forms), response regulator OmpR, and membrane fusion protein. Of these proteins, GroES was identified as a dominant GC-related antigen with a much higher seropositivity of GC samples (64.2%, n = 95) compared with 30.9% for gastritis (n = 94) and 35.5% for DU (n = 124). GroES seropositivity was more commonly associated with antral GC than with non-antral GC (odds ratio = 2.7; 95% confidence interval, 1.1-6.7). In peripheral blood mononuclear cells, GroES stimulated production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor, IL-1beta, tumor necrosis factor-alpha, cyclooxygenase-2, and prostaglandin E(2). Moreover when incubated with gastric epithelial cells, GroES induced expression of IL-8, cell proliferation, and up-regulation of c-jun, c-fos, and cyclin D1 but caused down-regulation of p27(Kip1). We conclude that GroES of H. pylori is a novel GC-associated virulence factor and may contribute to gastric carcinogenesis via induction of inflammation and promotion of cell proliferation.
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PMID:Comparative immunoproteomics of identification and characterization of virulence factors from Helicobacter pylori related to gastric cancer. 1676 9

We investigated the modulating actions of the nonselective K(+) channel blocker 4-aminopyridine (4-AP) on amyloid beta (Abeta(1-42))-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of Abeta(1-42) (5 mum) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K(+) current (I(K)). Intracellular application of the nonhydrolyzable analog of GTP, GTPgammaS, induced an outward K(+) current with similar properties to the Abeta(1-42)-induced I(K) including sensitivity to 4-AP (IC(50) = 5 mm). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in Abeta(1-42)-treated microglia. Abeta(1-42) peptide also caused a slow, progressive increase in levels of [Ca(2+)](i) (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to Abeta(1-42) led to enhanced p38 mitogen-activated protein kinase and nuclear factor kappaB expression with factors inhibited by 4-AP. Abeta(1-42) also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from Abeta(1-42)-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of Abeta(1-42) into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an Abeta(1-42)-induced I(K) (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology.
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PMID:Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia. 1709 87

Increased podocyte cyclooxygenase-2 (COX-2) expression is seen in rats after renal ablation and Thy-1 nephritis and in cultured murine podocytes in response to mechanical stress. For investigation of whether COX-2 overexpression plays a role in podocyte injury, transgenic B6/D2 mice in which COX-2 expression was driven by a nephrin promoter were established. Selective upregulation of COX-2 expression in podocytes of transgenic mouse kidneys was confirmed by immunoblotting and immunohistochemistry. Whether upregulation of podocyte-specific COX-2 expression enhanced sensitivity to the development of Adriamycin nephropathy was examined. Adriamycin administration induced dramatically more albuminuria and foot process effacement and reduced glomerular nephrin mRNA and immunoreactivity in transgenic mice compared with wild-type littermates. Adriamycin also markedly increased immunoreactive COX-2 expression in podocytes from transgenic mice compared with the wild-type mice. Reverse transcriptase-PCR indicated that this increase represented a stimulation of endogenous COX-2 mRNA expression rather than COX-2 mRNA driven by the nephrin promoter. Balb/C mice, which are susceptible to renal injury by Adriamycin, also increased podocyte COX-2 expression and reduced nephrin expression in response to administration of the drug. Long-term treatment with the COX-2-specific inhibitor SC58236 ameliorated the albuminuria that was induced by Adriamycin in the transgenic mice. SC58236 also reduced Adriamycin-induced foot process effacement in both the COX-2 transgenic mice and Balb/C mice. Therefore, overexpression of COX-2 may predispose podocytes to further injury.
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PMID:Overexpression of cyclooxygenase-2 predisposes to podocyte injury. 1725 95

Recent evidence suggests that retinopathy of prematurity, a potentially blinding condition of premature human neonates, has a genetically-determined component. Different inbred strains of rat exhibit differential susceptibility to oxygen-induced retinopathy (OIR), a well-established experimental model of retinopathy of prematurity. To explore the basis for this differential susceptibility, we quantified the retinal expression of 8 angiogenesis-related genes during early post-natal retinal development in rats with OIR. Inbred Fischer 344 (F344), Dark Agouti (DA) and Sprague Dawley (SPD) rat neonates were exposed to alternating cycles of 80% oxygen in air and normoxia for up to 14 days. After 14 days of cyclic hyperoxic exposure, some rats were exposed to normoxia for a further 4 days. Retinal mRNA for vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), pigment epithelium-derived factor (PEDF), angiopoietin-2 (Ang2), Tie2, cyclooxygenase-2 (COX2), insulin-like growth factor-1 (IGF1) and erythropoietin (EPO) were quantified by real-time reverse-transcriptase polymerase chain reaction at different time-points. Time-course analysis showed that expression of mRNA for VEGF, VEGFR2 and Ang2 was significantly greater in OIR-resistant (F344) retinae than in OIR-susceptible (DA) retinae during the first 9 days of cyclic hyperoxia. However, at post-natal days 14 and 18, retinal mRNAs for VEGF, EPO, VEGFR2, Ang2, IGF1, COX2 and PEDF were expressed to a significantly greater extent in OIR-susceptible (DA, SPD) than OIR-resistant (F344) retinae. The VEGF/PEDF ratio was greater in the F344 compared with the DA strain up to day 9, but was higher in the DA than the F344 strain at days 14 and 18. Thus, we found that retinal expression of angiogenesis-related genes was significantly higher in OIR-resistant rats than in OIR-susceptible rats during early retinal development, but the pattern reversed during the proliferative phase of OIR. We conclude that susceptibility to OIR correlates with differential gene expression very early in retinal microvascular development, during periods of cyclic hyperoxic exposure rather than during subsequent sustained hypoxia.
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PMID:Kinetics of strain-dependent differential gene expression in oxygen-induced retinopathy in the rat. 1769 14


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